The Borrelia are the causative agents of several important human and animal infections including Lyme disease and relapsing fever. Recent studies from our lab and others have demonstrated that some species of the Lyme disease spirochetes bind the complement regulatory protein, factor H (fH). FH bound on the cell surface is able to interact with factor I and facilitate the efficient cleavage of the critical complement component C3b. In the context of bacterial pathogenesis, this cleavage event serves to protect the bacteria from opsonization and the alternate complement cascade. The relapsing fever spirochetes (RFS) are able to persist in their mammalian hosts for extended periods of time. Some species achieve high cell densities in the blood while others tend to invade the CNS. The ability to survive in the blood suggests that these bacteria are also able to circumvent complement. We have recently identified and characterized a new and novel fH binding protein (FHBP) in B. hermsii that we call FhbA (fH-binding protein A). In this proposal we will investigate the molecular interactions between FhbA and human fH and investigate the contribution of FhbA in pathogenesis through gene inactivation.